Difluoro statone antiviral analogs

ABSTRACT

This invention relates to novel statone antiviral analogs, to the processes and intermediates useful for their preparation and to their use as antiviral agents.

This is a continuation of application Ser. No. 08/596,336, filed Feb.20, 1996, now U.S. Pat. No. 5,831,094 which is a 371 of PCT/US94/09053,filed Aug. 10, 1994, which are herein incorporated by reference.

This invention relates to novel statone antiviral analogs, to theprocesses and intermediates useful for their preparation and to theiruse as anti-viral agents.

BACKGROUND OF THE PRESENT INVENTION

Retroviruses are a class of viruses which transport their geneticmaterial as ribonucleic acid rather than as deoxyribonucleic acid.Retroviruses are associated with a wide variety of diseases in man, oneof which is AIDS. Although there have been disclosures of otheranti-viral agents useful in the treatment of AIDS, for example seepatent applications EP 0 218 688, EP 0 352 000 and PCT/US 91/09741, thecompounds of the present invention have not been previously disclosed.PCT/US 91/09741 is hereby incorporated by reference.

DESCRIPTION OF THE PRESENT INVENTION

More specifically this invention relates to novel difluoro statoneanalogs of Formula 1 ##STR1## and the stereoisomers, hydrates, isosteresand the pharmaceutically acceptable salts thereof wherein

P₁ is ##STR2## wherein T is (O)_(b) --W--R! and T' is (O)_(b) '--W'--R'!or H, wherein each of W and W' are independently C₁₋₆ alkylene ornothing,

provided that W is C₂₋₆ alkylene when W is directly attached to anitrogen atom in R,

provided that W' is C₂₋₆ alkylene when W' is directly attached to anitrogen atom in R';

P₂ is C₁₋₆ alkyl, cyclopentyl, hydroxy C₁₋₆ alkyl, phenyl, benzyl or3-tetrahydrofuryl;

R and R' are each independently C₂₋₆ alkenylene, piperazinyl,substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, orpyrimidinyl, wherein substituted piperazinyl is piperazinyl substitutedon one nitrogen atom thereof with CHO, C(O)NHR₄, C₁₋₄ alkyl or CO₂ R₄ ;

R₁ is benzyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, phenyl, benzyl, phenethyl,fluorenylmethylenoxy, 2-quinolinyl, PDL, ##STR3## NHSO₂ R₄,N(R₄)(benzyl), or N(R₄)(PDL); PDL is --(CH₂)_(a) -2-, 3-, or 4-pyridyl,or 2-substituted benzyloxy, wherein the substitution is with a nitro,OH, amino, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkylene, or halogeno;

R₃ is C₁₋₆ alkenyl, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkyl, C₁₋₆ alkyl, or OH;

R₄ is H, C₁₋₆ alkyl, phenyl or benzyl;

R₅ is H, C₁₋₆ alkyl, OH, C₁₋₆ alkoxy, ##STR4## .paren open-st.C₁₋₆alkylene.paren close-st.OR₄ or --CH(Y)(Z), Y being C₁₋₆ hydroxyalkylene, C₁₋₆ alkyl, or (CH₂ .paren close-st._(e) --C₆ H₄ .parenopen-st.V)_(e), and

Z being CHO, CO₂ R₄, CO₂ NHR₄ or (CH₂ .paren close-st._(e) --OR₄, and

V being OR₄ or hydroxy C₁₋₆ alkylene;

R₆ is as defined for R₅ with the proviso that R₆ is other than H when R₅is H, and when R₅ and R₆ are taken together with nitrogen atom to whichthey are attached form a heterocyclic moiety of the formulae ##STR5## R₇is CH₂ OR₄ or C(O)NHR₄, CHO, R₈ is (H,OH) or ═O;

a is zero, 1, 2 or 3;

b and b' are each independently zero or 1;

d and d' are each independently 1 or 2;

e and e' are each independently zero, 1 or 2; and

x is zero or one.

Isosteres of the compounds of Formula I include those wherein (a) theα-amino acid residues of the P₁ and P₂ substituents are in theirunnatural configuration (when there is a natural configuration) or (b)when the normal peptidic carbamoyl linkage is modified, such as forexample, to form --CH₂ NH-- (reduced), ##STR6## --COCH₂ -- (keto),--CH(OH)CH₂ -- (hydroxy), --CH(NH₂)CH₂ -- (amino), --CH₂ CH₂ --(hydrocarbon). Preferably a compound of the invention should not be inan isosteric form. Unless otherwise stated the α-amino acids arepreferably in their L-configuration.

A compound of the invention may be in free form, e.g., amphoteric form,or in salt, e.g., acid addition or anionic salt, form. A compound infree form may be converted into a salt form in an art-known manner andvice-versa.

The pharmaceutically acceptable salts of the peptide of Formula I (inthe form of water, or oil-soluble or dispersible products) include theconventional non-toxic salts or the quaternary ammonium salts of thesepeptides, which are formed, e.g., from inorganic or organic acids orbases. Examples of such acid addition salts include acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, paemoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Base salts include ammonium salts, alkalimetal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups may be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

The hydrates of the compounds of Formula I are hydrated compounds havingthe partial structure ##STR7## and in their end-use application aregenerally the active forms.

In general, as used herein, the term "alkyl" includes the straight,branched-chain and cyclized manifestations thereof unless otherwiseindicated, particularly such moieties as methyl, ethyl, isopropyl,n-butyl, t-butyl, --CH₂ -t-butyl, cyclopropyl, n-propyl, pentyl,cyclopentyl, n-hexyl, cyclohexyl and cyclohexylmethyl. The term"aralkyl", when used, includes those aryl moieties attached to analkylene bridging moiety, preferably methyl or ethyl.

"Aryl" includes both carbocyclic and hetereocyclic moieties of whichphenyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, furyl andthienyl are of primary interest; these moieties being inclusive of theirposition isomers such as, for example, 2-, 3-, or 4-pyridyl, 2- or3-furyl and thienyl, 1-, 2-, or 3-indolyl or the 1- and 3-indazolyl, aswell as the dihydro and tetrahydro analogs of the furyl and thienylmoieties. Also included within the term "aryl" are such fusedcarbocyclic moieties as pentalenyl, indenyl, naphthalenyl, azulenyl,heptalenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl,anthracenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl,chrysenyl and naphthacenyl. Also included within the term "aryl" aresuch other heterocyclic radicals as 2- or 3-benzo b!thienyl, 2- or3-naphtho 2,3-b!thienyl, 2- or 3-thianthrenyl, 2H-pyran-3-(or 4- or5-)yl, 1-isobenzo-furanyl, 2H-chromenyl-3-yl, 2- or 3-phenoxathiinyl, 2-or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl,3-pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl,3-isoquinolyl, 2-quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl,2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-pteridinyl,4aH-carbazol-2-yl, 2-carbazolyl, β-carbolin-3-yl, 3-phenanthridinyl,2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl,2-phenothiazinyl, 3-isoxazolyl, 2-phenoxazinyl, 3-isochromanyl,7-chromanyl, 2-pyrrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl,2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl,1-indolinyl, 1-isoindolinyl, 3-morpholinyl, benzo b!isoquinolinyl andbenzo b!furanyl, including the position isomers thereof except that theheterocyclic moieties cannot be attached directly through their nitrogenone, two or three substituents independently selected from C₁₋₆ alkyl,haloalkyl, alkoxy, thioalkoxy, aminoalkylamino, dialkylamino, hydroxy,halo, mercapto, nitro, carboxaldehide, carboxy, carboalkoxy andcarboxamide.

Likewise the term "alkylene" (a divalent alkane radical) includesstraight or branched-chain moieties. Some examples of branched-chainalkylene moieties are ethylethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, and so on. For example, C₃ alkylene can mean##STR8##

All (C₁₋₆) moieties such as C₁₋₆ alkyl, C₁₋₆ alkylene, C₂₋₆ alkenylene,C₁₋₆ alkoxy, and hydroxy C₁₋₆ alkyl, are more preferably C₁₃ moieties(containing 1-3 carbon atoms instead of 1-6 carbon atoms, morepreferably a C₁₋₂ moiety and most preferably a C₁ moiety). "Alkenylene"(divalent unsaturated moiety) can also mean "Alkenyl" such as ethenyl(univalent unsaturated moiety).

The fluorenylmethyloxy moiety is that moiety generally called by itsabbreviation FMOC, and is the fluorenyl moiety bearing --CH₂ O attachedto the 9-position of the fluoroenyl moiety. Other terms defined hereinare ##STR9## the substitution (★) occurring only at one nitrogenmolecule which is not attached to the remainder of the molecule(attachment via a nitrogen atom). The substituents are one of CHO,C(O)NHR₄, C₁₋₄ alkyl or CO₂ R₄. Piperidyl and morpholinyl both bind tothe rest of the ##STR10## molecule via their respective nitrogen atomswhile pyrimidinyl, pyridyl and pyrazinyl bind to the rest ##STR11## ofthe molecule anywhere except their respective nitrogen atoms.

More specifically, in the instance wherein P₂ is either C₁₋₆ alkyl orhydroxy C₁₋₆ alkyl, such moieties as --C(CH₃)₃, --CH(CH₃)₂, --CH(CH₃)(C₂H₅), --C(OH)(CH₃)₂ and --CH(OH)CH₃ are preferred. The "hydroxy C₁₋₆alkyl" moiety is illustrated in one example by --CH₂ --OH, the "C₁₋₆alkoxy C₁₋₆ alkyl" moiety, is illustrated in one example by --CH₂--OCH₃, (although in each instance the C₁₋₆ alkylene may be straight orbranched and the hydroxy radical is not limited to the terminal carbonatom of the alkyl moiety).

As it is often quite advantageous to have what is termed an aminoprotecting group (Pg), the scope of those compounds of Formula I,includes those R₁ moieties which, together with their adjacent carbonylmoiety form such groups as acetyl (Ac), succinyl (Suc), benzoyl (Bz),t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBZ), tosyl (Ts), dansyl(DNS), isovaleryl (Iva), methoxysuccinyl (MeOSuc), 1-adamantanesulphonyl(AdSO₂), 1-adamantaneacetyl (AdAc), phenylacetyl, t-butylacetyl (Tba),bis (1-naphthyl)methyl!acetyl (BNMA) and Rz wherein Rz is an aryl groupas previously described suitably substituted by 1 to 3 members selectedindependently from the group consisting of fluoro, chloro, bromo, iodo,trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, alkoxycontaining from 1 to 6 carbons, carboxy, alkylcarbonylamino wherein thealkyl group contains 1 to 6 carbons, 5-tetrazolo, and acylsulfonamido(i.e., acylaminosulfonyl and sulfonylaminocarbonyl) containing from 1 to15 carbons, provided that when the acylsulfonamido contains an aryl. Thearyl may be further substituted by a member selected from fluoro,chloro, bromo, iodo and nitro.

In those instances wherein there is an Rz moiety, it is preferred thatRz represent acylsulfonamido, particularly those wherein theacylsulfonamido contains an aryl moiety (preferably phenyl) substitutedby a halogen. The preferred Rz moieties being 4-(4-chlorophenyl)sulfonylaminocarbonyl!phenylcarbonyl, 4-(4-bromophenyl)sulfonylamino carbonyl!-phenylcarbonyl and 4-phenylsulfonylamino carbonyl!-phenylcarbonyl (said moieties beingabbreviated as 4-Cl-.o slashed.-SAC-Bz, 4-Br-.o slashed.-SAC-Bz and .oslashed.-SAC-Bz, respectively).

Among the classes of amino protecting groups contemplated are: (1) acyltype protecting groups such as formyl, trifluoroacetyl, phthalyl,p-toluenesulfonyl (tosyl), benzenesulfonyl, nitrophenylsulfenyl,tritylsulfenyl, O-nitrophenoxyacetyl, and α-chlorobutyryl; (2) aromaticurethane type protecting groups such as benzyloxycarbonyl andsubstituted benzyloxycarbonyls such as p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl,α-,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, and benzhydryloxycarbonyl;(3) aliphatic urethane protecting groups such as tert-butyloxycarbonyl(Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,and allyloxycarbonyl; (4) cycloalkyl urethane type protecting groupssuch as cyclopentyloxycarbonyl, adamantyloxycarbonyl, andcyclohexyloxycarbonyl; (5) thio urethane type protecting groups such asphenylthiocarbonyl; (6) alkyl type protecting groups such astriphenylmethyl (trityl) and benzyl (Bzl); (7) trialkylsilane protectinggroups such as trimethylsilane if compatible. The preferred α-aminoprotecting groups are tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl(CBZ). The use of Boc as an α-amino protecting group for amino acids isdescribed by Bodansky et al. in "The Practice of Peptide Synthesis",Springer-Verlag, Berlin (1984), p. 20.

In general the compounds of this invention may be prepared usingstandard chemical reactions analogously known in the art.

In the instance wherein it is desired to prepare compounds of theformula ##STR12## wherein R₁, P₂, P₁, R₅ and R₆ are as previouslydefined, the process outlined by the following reaction schemes mayadvantageously be utilized. ##STR13##

In effecting reaction scheme A, A' or A", the process is initiated byconducting a Reformatsky-type reaction wherein an aldehyde of Formula(3) is subjected to a condensation reaction with an ester ofbromodifluoroacetic acid, preferably the ethyl ester in the presence ofzinc and in an anhydrous aprotic solvent, e.g., tetrahydrofuran, ether,dimethoxyethane and the like under a nitrogen or argon inert atmosphere.The reaction is gently heated to about 60° C. for about 1-12 hours orultrasonicated to produce compounds (4).

Step (b) to obtain compounds (5) or (14) may be effected directly orundirectly. In one instance, the esters of Formula (4) or (13) arede-esterified using a strong base (LiOH, KOH, NaOH and the like) in thepresence of water using a partially water miscible solvent (such astetrahydrofuran, dimethoxyethane, dioxane) at about room temperature.The so-obtained de-esterified compound is then aminated with theappropriate R₅ R₆ -substituted amine using a peptide-like couplingprocedure--i.e., using a mixed anhydride method using DCC andhydroxybenzotriazole at room temperature in solvents such as CH₂ Cl₂,tetrahydrofuran or dimethylformamide. Alternatively the esters (4) or(13) may be directly subjected to a reaction with the appropriate R₅ R₆-substituted amine without or with a solvent (tetrahydrofuran) at about80° C.

In Step (c) Compounds (6), (8) or (11) are prepared by removal of theP"₁ protecting group using standard procedures, e.g., hydrogenation. Thefree phenol functionality is then reacted with an appropriate alkylhalide in an inert solvent (preferably anhydrous dioxane or anhydrousdimethylformamide) in the presence of a base (potassium or cesiumcarbonate) with or without potassium iodide at room or refluxtemperature.

In Step (c1) compound (13) is prepared by removal of the P"₁ protectinggroup using standard procedures, e.g., hydrogenation, P_(OH) being thecompound obtained. P_(OH) being a free phenol.

In Step (c2) compounds (6), (8) or (11) are prepared from the P_(OH)derivatives (14), (16) or (17) by reaction with an appropriatealkylhalide in an inert solvent, in the presence of a base.

In Step (d), for the preparation of Compounds (7), (9) and (15), theprotecting groups Pg may readily be removed by standard procedurespreferably acid/base hydrolysis (e.g., formic acid at room temperaturefollowed by extraction of the free base after treatment with sodiumcarbonate).

In Step (e), Compounds (7), (9) or (15) are subjected to a peptidecoupling procedure with an appropriately protected acid of the formulaR₁ CONHCH(P₂)CO₂ H or R₁ CO₂ H, using the herein-described procedures(or by any other coupling procedure currently available, or described inEuropean Patent Application, Serial Number 93 401 785.6) to producecompounds (8) and (11) (from compound (7)); (10) and (12) (from compound(9)); and (16) and (17) (from compound (15)).

In Step (f), the oxidation may be effected via the well-known Swernoxidation procedure, or with1,1,1-tris-(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3(1H)-one. The latteris preferred when more than one basic group is present in the alcoholprecursors (8) or (11). The oxidation procedures are effected accordingto standard procedures well known in the art.

In general the Swern oxidation see Synthesis, (1981), 165! is effectedby reacting about 2 to 20 equivalents of dimethylsulfoxide (DMSO) withabout 1 to 10 equivalents of trifluoromethylacetic anhydride (CF₃ CO)₂O! or oxalyl chloride (COCl)₂ !, said reactants being dissolved in aninert solvent, e.g., methylene chloride (CH₂ Cl₂), said reaction beingunder an inert atmosphere (e.g., nitrogen or equivalently functioninggas) under anhydrous conditions at temperatures of about -70° C. to -30°C. to form an in situ sulfonium adduct to which is added about 1equivalent of the appropriate alcohols, i.e., compounds (8) and (11).Preferably, the alcohols are dissolved in an inert solvent, e.g., CH₂Cl₂, tetrahydrofuran, or minimum amounts of DMSO, and the reactionmixture is allowed to warm to about -50° C. or -20° C. (for about 20-60minutes) and then the reaction is completed by adding about 3 to 30equivalents of a tertiary amine, e.g., triethylamine,diisopropylethylamine, N-methyl morpholine, etc.

Another alternative process for converting the alcohols to the desiredketones is an oxidation reaction which employs periodane (i.e.,1,1,1-tris(acetyl)oxy-1,2-benzodioxol-3(1H)-one), see Dess Martin, J.Org. Chem., 48, 4155, (1983)!. This oxidation is effected by contactingabout 1 equivalent of the alcohols with 1 to 5 equivalents of periodane(preferably 1.5 equivalents), said reagent being in suspension in aninert solvent (e.g., methylene chloride) under an inert atmosphere(preferably nitrogen) under anhydrous conditions at 0° C. to 50° C.(preferably room temperature) and allowing the reactants to interact forabout 1 to 48 hours. Optional deprotection of the amine protectinggroups may be effected as desired after the ketones have been isolated.

In general, the modified Jones oxidation procedure may conveniently beeffected by reacting the alcohols with pyridinium dichromate bycontacting the reactants together in a water-trapping molecular sievepowder, e.g., a grounded 3 Angstrom molecular sieve), wherein saidcontact is in the presence of glacial acetic acid at about 0° C. to 50°C., preferably at room temperature followed by isolation and thenoptionally removing amine protecting groups.

Alternatively, 1 to 5 equivalents of a chromic anhydride-pyridinecomplex (i.e., a Sarett reagent prepared in situ) see Fieser and Fieser"Reagents for Organic Synthesis" Vol. 1, pp. 145 and Sarett, et al.,J.A.C.S. 25, 422, (1953)! said complex being prepared in situ in aninert solvent (e.g., CH₂ Cl₂) in an inert atmosphere under anhydrousconditions at 0° C. to 50° C. to which complex is added 1 equivalent ofthe alcohols allowing the reactants to interact for about 1 to 15 hours,followed by isolation and optionally removing amine protecting groups.

For the preparation of the necessary aldehydes of formula (3), and thepreparation of the acids which are to be coupled with the amines ofFormula (7), (9) or (15) alternative alkylation procedures are utilizeddepending upon whether the P₁ and/or the P₂ moieties are or are notresidues of natural amino acids. The preparation of these intermediateswherein the P₁ or P₂ moieties are residues of natural amino acids (orminor modifications thereof, e.g., P₁ or P₂ being a benzyl or methylether of tyrosine), the compounds are either known or are prepared byprocesses and techniques well known in the art.

To prepare the intermediates of the formula ##STR14## wherein Pg is anamino protecting group, P₃ is either a P'₁ or P'₂ moiety with P'₁ andP'₂ being as defined for P₁ and P₂ respectively, except that they areother than residues of naturally occuring amino acids, and the R_(g)moiety is an alkyl radical, preferably methyl when P₃ is P'₁, and ethylwhen P₃ is P'₂, alternative methods are available.

To prepare the intermediates of formula ##STR15## the following reactionscheme may be utilized ##STR16## wherein P₃ is as previously defined andX is a leaving group, preferably halo or triflate, R₉ is methyl when P₃is P'₁ and ethyl when P₃ is P'₂.

In essence, the preparation of compounds (19) utilizes the Krapchomethod Tetrahedron Letters, 26, 2205 (1976)! for alkylation whereincompounds (18) are treated with a base, e.g., LDA, (lithiumdiisopropylamide), followed by reaction with the desired P₃ X in thepresence of TMEDA (i.e. tetramethylethylenediamine) in a solvent(tetrahydrofuran) with or without HMPA (i.e. hexamethylphosphoramide)according to the standard Krapcho conditions. Following alkylation thecompounds are then subjected to a reduction using diisobutylaluminiumhydride (Dibal) in a mixture of solvents, e.g., ether, toluene, hexane,tetrahydrofuran at about -78° C. for about 1 hour. Following thepreparation of the aldehydes of Formula (10B), the compounds aresubjected to the processes of Reaction Schemes A, A' and/or A".

Alternatively, the compounds of (19) may be prepared by aMalonate/Curtius type sequence of reactions, see Yamada, et al., J.Amer. Chem. Soc., (1972) 94, 6203! as illustrated by the followingreaction scheme ##STR17## wherein t-Bu is t-butyl, although otherselectively removal acid protecting groups may be utilized, and P₃ X isas previously defined. This reaction involves the alkylation of themalonate ester (20) followed by selective removal of the t-butylprotecting group to produce compounds (22).

These compounds are then transformed to (19) using the Curtius typerearrangement which entails their conversion to the protected amine viathe intermediately formed azides, isocyanates, amines which are thenprotected with standard amino protecting groups, preferentially beingprotected in situ.

In the instance wherein P₃ represents a P'₁ moiety, the ester istransformed to the desired aldehydes of Formula (3) using standard Dibalreduction techniques, particularly in this situation (wherein P₁ is nota residue of a natural amino acid). Alternatively, (as is preferred whenP₁ is a residue of a natural amino acid) the ester is de-esterified toits corresponding acid, converted to its corresponding hydroxamate andthe hydroxamate upon treatment with lithium aluminum hydride isconverted to its aldehyde. In the instance wherein P₃ represents a P'₂moiety, the ethyl ester of compounds (19) are removed and the resultingcompounds are ready for coupling as outlined in Reaction Scheme A'.

Having generically described the methods for the preparation of thecompounds of this invention, the following specific examples illustratethe chemistry and techniques by which the synthesis may be effected.

The following examples present typical syntheses as described in SchemesA, A' or A". These examples are understood to be illustrative only andare not intended to limit the scope of the present invention in any way.As used herein, the following terms have the indicated meanings: "g"refers to grams; "mmol" refers to millimoles; "ml" refers tomilliliters; "bp" refers to boiling point; "mp" refers to melting point;"°C." refers to degrees Celsius; "mm Hg" refers to millimeters ofmercury; "μl" refers to microliters; "μg" refers to micrograms; and "μM"refers to micromolar; "Cbz" means carbobenzyloxy.

EXAMPLE 1 4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Oxo-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide ##STR18## StepA:

4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-54-Benzyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-(4-benzyloxy)phenyl!pentanoic acid, ethyl ester, compound described inPatent Application PCT/US91/09741, filed Dec. 20, 1991 incorporatedherein by reference, (4.79 g, 10 mmol) in anhydrous tetrahydrofuran (25ml) was added benzylamine (6.42 g, 60 mmol). The mixture was stirred atroom temperature overnight. The crude mixture was diluted with ethylacetate (150 ml), washed with 0.1N aqueous hydrochloric acid (3×50 ml),water (50 ml) and brine (50 ml). The organic layer was dried overanhydrous magnesium sulphate.

After filtration and removal of the solvent in vacuo the residue waspurified by flash chromatography.(silica gel, ethyl acetate/cyclohexane:2:8) to give the title compound (3.80 g, 71% yield). Rf: 0.47 (ethylacetate/cyclohexane) mp: 142° C. MS: MH!⁺ =541 MNH₄ !⁺ =558 Analysis:for C₃₀ H₃₄ N₂ 0₅ F₂, Calculated: C, 66.65; H, 6.34; N, 5.18 Found: C,66.96; H, 6.34; N, 5.15.

STEP B:

4-Amino-2,2-Difluoro-3-Hydroxy-5 (4-Benzyloxy)Phenyl!N-BenzylPentanamide

A solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5(4-benzyloxy)phenyl!N-benzyl pentanamide (0.65 g, 1.2 mmol) in formicacid (20 ml) was stirred at room temperature for 4 hours. The solventwas removed in vacuo. The residue was dissolved in ethyl acetate (60 ml)and washed with a saturated solution of sodium carbonate (3×10 ml), andbrine (10 ml). The organic layer was dried over magnesium sulphate.

Filtration and removal of the solvent in vacuo yielded the titlecompound as a white solid (0.42 g, 80% yield) used without furtherpurification in the next step. Rf: 0.62 (AcOH/nBuOH/H₂ O: 2:6:2 MS: MH!⁺=441 Analysis: for C₂₅ H₂₆ N₂ O₃ F₂, Calculated: C, 68.17; H, 5.95; N,6.36 Found: C, 67.88; H, 5.88; N, 6.56.

STEP C:

4(N-Tert-Butoxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-5(4-Benzyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of N-tert-butoxycarbonyl-L-valyl-anhydride (0.387 g, 0.93mmol) in anhydrous dichloromethane (10 ml) at room temperature, wasadded a solution of 4-amino-2,2-difluoro-3-hydroxy-5(4-benzyloxy)phenyl!N-benzyl pentanamide (0.41 g, 0.93 mmol) inanhydrous N,N-dimethylformamide (3 ml) and anhydrous dichloromethane (2ml). The mixture was stirred at room temperature overnight.

Evaporation and purification of the residue by flash chromatography(silica gel, gradient of ethyl acetate/cyclohexane: 2:8 to 1:1) affordeda white solid (0.45 g, 76% yield). Rf: 0.38 (AcOEt/cyclohexane: 1:1) MS:MH!⁺ =640 Analysis: for C₃₅ H₄₃ N₃ O₆ F₂, Calculated: C, 65.71; H, 6.77;N, 6.57 Found: C, 65.92; H, 6.87; N, 6.45.

STEP D:

4(N-Tert-Butoxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-5(4-(Hydroxy)Phenyl!N-Benzyl Pentanamide

To a solution of4(N-tert-butoxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxy-5(4-benzyloxy)phenyl!N-benzyl pentanamide (0.35 g, 0.55 mmol) in absoluteethanol (15 ml) and anhydrous N,N-dimethylformamide (5 ml) was added 10%Palladium in activated charcoal (0.1 g). This mixture was stirred atroom temperature under atmospheric pressure of hydrogen overnight.

Filtration of the catalyst and evaporation in vacuo yielded 90% of thetitle compound (0.27 g) as a white solid. Rf: 0.29 (ethylacetate/cyclohexane: 1:1).

STEP E:

4(N-Tert-Butoxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of4(N-tert-butoxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxyl-54(hydroxy)phenyl!N-benzyl pentanamide (0.27 g, 0.49 mmol) in anhydrousdioxane (20 ml) was added anhydrous cesium carbonate (0.422 g, 1.3mmol), potassium iodide (0.01 g) and N-(2-chloroethyl) morpholinehydrochloride (0.111 g, 0.6 mmol). This mixture was heated under refluxfor 72 hours. The crude mixture was diluted with ethyl acetate (100 ml)and washed three times with water and brine. The organic layer was driedover magnesium sulphate.

Filtration and evaporation of the solvent in vacuo afforded a residuewhich was purified by flash chromatography (silica gel, ethyl acetate).The title compound was obtained with 62% yield (0.2 g). Rf: 0.33 (CHCl₃/CH₃ OH: 92:8) MS: MH!⁺ =663.

STEP F:

4(L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide

A solution of4(N-tert-butoxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-benzyl pentanamide (0.19 g, 0.28mmol) in formic acid (15 ml) was stirred at room temperature for 4hours. After evaporation of the solvent in vacuo, the residue wasdiluted with ethyl acetate (50 ml) and washed three times with asaturated solution of sodium carbonate (3×10 ml) and brine (10 ml). Theorganic layer was dried over magnesium sulphate.

Filtration and removal of the solvent in vacuo yielded the titlecompound as a white solid used without purification in the next step(0.11 g, 69% yield).

STEP G:

4(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of 4(L-valyl)amino-2,2-difluoro-3-hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-benzyl pentanamide (0.1 g, 0.18mmol) in anhydrous dichloromethane (10 ml) was added benzyldicarbonate(0.055 g, 0.19 mmol). The mixture was stirred at room temperatureovernight.

Evaporation of the solvent in vacuo, purification of the residue byflash chromatography (silica gel, CH₂ Cl₂ /CH₃ OH:99:1) andrecrystallization (ethyl acetate/pentane) afforded the title compound asa white solid (0.075 g, 60% yield). Rf: 0.38 (chloroform/methanol: 92:8)MS: MH!⁺ =697 Analysis: for C₃₇ H₄₆ N₄ O₇ F₂, Calculated with 0.25 H₂ O:C, 63.77; H, 6.68; N, 7.98 Found: C, 63.34; H, 6.64; N, 8.08.

STEP H:

4(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Oxo-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of oxalyl chloride (0.102 g, 0.8 mmol) in anhydrousdichloromethane (1 ml) at -60° C., was added under nitrogen, dimethylsulfoxide (distilled over calcium hydride) (0.125 g, 1.6 mmol) inanhydrous dichloromethane (1 ml). After 10 minutes stirring a solutionof 4(N-benzyloxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-benzyl pentanamide (0.06 g, 0.08mmol) in anhydrous dichloromethane (3 ml) was added. The mixture wasstirred at -60° C. for 3 hours and the temperature was then allowed torise to -10° C. Triethylamine (0.101 g, 1 mmol) in anhydrousdichloromethane (1 ml) was then added. The mixture was stirred for 15hours while the temperature was allowed to rise to room temperature. Thecrude mixture was taken off in ethyl acetate (30 ml) and washed with0.1N aqueous hydrochloric acid (3×8 ml), brine (8 ml) and dried overmagnesium sulphate.

Filtration and removal of the solvent in vacuo yielded a crude residuewhich was purified by flash chromatography (silica gel,chloroform/methanol: 99:1). The title compound was isolated as a whitesolid (0.036 g, 61% yield). Rf: 0.40 (chloroform/methanol: 92:8) MS:MH!⁺ =695 Analysis: for C₃₇ H₄₄ N₄ O₇ F₂, Calculated: C, 63.96; H, 6.38;N, 8.06 Found: C, 64.10; H, 6.50; N, 7.65 ¹⁹ F NMR: shows mixture of twostereoisomers (40/60) and ketone/hydrate: 75/25.

EXAMPLE 2 4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Oxo-54({2-Pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide ##STR19## STEP A:

4-Tert-Butoxycarbonylamino-2, 2-Difluoro-3-Hydroxy-5(4-Hydroxy)Phenyl!N-Benzyl Pentanamide

A solution of 4-(tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-(4-benzyloxy)phenyl!N-benzyl-pentanamide (1.90 g, 3.5 mmol) in absoluteethanol (100 ml) was stirred with 10% Palladium on charcoal (0.6 g) atroom temperature under atmospheric pressure of hydrogen overnight.

Filtration of the catalyst and evaporation in vacuo of the filtrate,yielded 89% of the title compound (1.40 g) as a white solid. Rf: 0.38(ethyl acetate/cyclohexane) Analysis: for C₂₃ H₂₈ N₂ O₅ F₂, 0.25 H₂ O:Calculated: C, 60.72; H, 6.31; N, 6.16 Found: C, 60.60; H, 6.25; N,6.03.

STEP B:

4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-54({2-pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide

To a solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5(4-hydroxy)phenyl!N-benzyl pentanamide (0.59 g, 1.3 mmol) in anhydrousdioxane (25 ml) was added anhydrous cesium carbonate (1.11 g, 3.4 mmol),potassium iodide (0.01 g) and 2-picolylchloride hydrochloride (0.246 g,1.5 mmol). This mixture was heated under reflux for 6 hours. The crudemixture was diluted with ethyl acetate (150 ml) and washed three timeswith water and once with brine. The organic layer was dried overmagnesium sulphate.

Filtration and evaporation in vacuo of the solvent afforded a residuewhich was purified by flash chromatography (silica gel, gradient ofethylacetate/cyclohexane: 3:7 to 1:1). The title compound was isolatedwith 40% yield (0.23 g). Rf: 0.49 (AcOEt/cyclohexane: 1:1) MS: MH!⁺=542.

STEP C:

4-Amino-2,2-Difluoro-3-Hydroxy-5 4({2-pyridyl}methyloxy)phenyl!N-BenzylPentanamide

A solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-54({2-pyridyl}methyloxy)phenyl!N-benzyl pentanamide (0.28 g, 0.52 mmol)in formic acid (25 ml) was stirred at room temperature for 4 hours. Thesolvent was removed in vacuo. The residue was dissolved with ethylacetate (60 ml) and washed with a saturated solution of sodium carbonate(3×20 ml) and brine, then dried over magnesium sulphate.

Filtration and removal of the solvent in vacuo yielded the titlecompound as a white solid (0.17 g, 75% yield) used without purificationin the next step.

STEP D:

4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-54({2-pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide

To a solution of Cbz-L-valyl-anhydride (0.184 g, 0.38 mmol) in anhydrousdichloromethane (8 ml) was added 4-amino-2,2-difluoro-3-hydroxy-54({2-pyridyl}methyloxy)phenyl!N-benzyl pentanamide (0.17 g, 0.38 mmol)in anhydrous dichloromethane (3 ml) and anhydrous N--N dimethylformamide(1 ml). This mixture was stirred at room temperature overnight.

The solvent was removed in vacuo and the residue purified by flashchromatography (silica gel, gradient of ethyl acetate/cyclohexane: 3:7to 75:25). The title compound was isolated as a white solid (0.195 g,76% yield). Rf: 0.45 (ethyl acetate) MS: MH!⁺ =675 Analysis: for C₃₇ H₄₀N₄ O₆ F₂, Calculated: C, 64.15; H, 6.11; N, 8.09 Found: C, 64.31; H,6.05; N, 7.96 ¹⁹ F NMR: shows mixture of 2 diastereoisomers 85/15.

STEP E:

4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Oxo-54({2-pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide

To a solution of oxalyl chloride (0.303 g, 2.5 mmol) in anhydrousdichloromethane (3 ml) at -60° C. under nitrogen, was added a solutionof dimethylsulfoxide (0.39 g, 5 mmol) in anhydrous dichloromethane (1ml). After stirring for 10 minutes, a solution of4-(N-benzyloxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxy-54({2-pyridyl}methyloxy)phenyl!N-benzyl pentanamide (0.17 g, 0.25 mmol)in anhydrous dichloromethane (4 ml) was added. The mixture was stirredat -60° C. under nitrogen for 3 hours and the temperature was thenallowed to rise to -10° C. Triethylamine (0.303 g, 3 mmol) in anhydrousdichloromethane (1 ml) was then added. The mixture was stirred for 15hours while the temperature was allowed to rise to room temperature. Thecrude mixture was taken off in ethyl acetate (50 ml) and washed with0.1N aqueous hydrochloric acid (3×10 ml). The organic layer was washedwith water, brine and dried over magnesium sulphate.

After filtration and removal of the solvent in vacuo the residue waspurified by flash chromatography (silica gel, gradient of ethylacetate/cyclohexane: 4:6 to 75:25). The title compound was isolated as awhite solid (0.09 g, 53% yield). Rf: 0.50 (AcOEt) MS: MH!⁺ =673Analysis: for C₃₇ H₃₈ N₄ O₆ F₂, Calculated: C, 66.06; H, 5.69; N, 8.33Found: C, 66.12; H, 5.77; N, 8.15 ¹⁹ F NMR: shows mixture of 2stereoisomers 40/60.

EXAMPLE 3 4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Oxo-5-4-(4-Pentenyloxy)Phenyl!N-Benzyl Pentanamide ##STR20## STEP A:

4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-54-(4-Pentenyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of the compound described in Example 2, Step A (0.45 g, 1mmol) in anhydrous dioxane (15 ml) was added anhydrous potassiumcarbonate (0.116 g, 1.2 mmol), potassium iodide (0.01 g) and5-bromo-1-pentene (1.64 g, 11 mmol). The mixture was heated under refluxfor 3 days.

The crude mixture was diluted with ethyl acetate (100 ml) and washedthree times with water and once with brine. The organic layer was driedover magnesium sulphate.

Filtration and evaporation in vacuo of the solvent afforded a residue,which was purified by flash chromatography (silica gel, gradient ofethyl acetate/cyclohexane 1:9 to 2:8). The title compound was isolatedas a white solid with 31% yield (0.16 g). Rf: 0.53 (AcOEt/cyclohexane:1:1) MS: MH!⁺ =519 MNH₄ !⁺ =536.

STEP B:

4-Amino-2,2-Difluoro-3-Hydroxy-5 4-(4-Pentenyloxy)Phenyl!N-BenzylPentanamide

A solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-54-(4-pentenyloxy)phenyl!N-benzyl pentanamide (0.16 g, 0.30 mmol) informic acid (10 ml) was stirred at room temperature for 4 hours. Thesolvent was removed in vacuo.

The residue was dissolved in ethyl acetate (60 ml) and washed threetimes with a saturated solution of sodium carbonate (3×20 ml) and brine(20 ml), then dried over anhydrous magnesium sulphate.

Filtration and removal of the solvent in vacuo yielded the titlecompound as a white solid (0.08 g, 63% yield) used without purificationin the next step.

STEP C:

4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-5-4-(4-Pentenyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of Cbz-L-Valyl anhydride (0.092 g, 0.20 mmol) in anhydrousdichloromethane (10 ml) was added 4-amino-2,2-difluoro-3-hydroxy-54-(oxo-4-pentenyl)phenyl!N-benzyl pentanamide (0.08 g, 0.19 mmol) inanhydrous dichloromethane (3 ml). The mixture was stirred at roomtemperature overnight.

The solvent was removed in vacuo and the residue purified by flashchromatography (silica gel, ethyl acetate/cyclohexane: 3:7).

The title compound was isolated as a white solid (0.09 g, 73% yield).Rf: 0.37 (ethyl acetate/cyclohexane: 1:1) MS: MH!⁺ =652.

STEP D:

4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Oxo-54-(4-Pentenyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of oxalyl chloride (0.178 g, 1.4 mmol) in anhydrousdichloromethane (10 ml) at -60° C. under nitrogen was added a solutionof anhydrous dimethyl sulfoxide (0.218 g, 2.8 mmol) in anhydrousdichloromethane (1 ml). After 10 minutes stirring a solution of4-(N-benzyloxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxy-54-oxo-(4-pentenyloxy)phenyl!N-benzyl pentanamide (0.09 g, 0.14 mmol) inanhydrous dichloromethane (3 ml) was added.

The mixture was stirred at -60° C. under nitrogen for 3 hours and thetemperature was then allowed to rise to -10° C. Triethylamine (0.162 g,1.6 mmol) in anhydrous dichloromethane (1 ml) was then added. Themixture was stirred for 15 hours while the temperature was allowed torise to room temperature.

The crude mixture was taken off in ethylacetate (50 ml) and washed with0.1N aqueous hydrochloric acid (3×10 ml). The organic layer was washedwith water, brine and dried over anhydrous magnesium sulphate.

After filtration and removal of the solvent in vacuo, the residue waspurified by flash chromatography (silica gel, ethyl acetate/cyclohexane2:8).

The title compound was obtained as a white solid (0.038 g, 43% yield).Rf: 0.39 (ethyl acetate/cyclohexane: 1:1) MS: MH!⁺ =650 MNH₄ !⁺ =667Analysis: for C₃₆ H₄₁ N₃ O₆ F₂, Calculated: C, 66.55; H, 6.36; N, 6.47Found: C, 65.75; H, 6.09; N, 5.79 ¹⁹ F NMR: shows mixture of 2stereoisomers 65/35 and ketone/hydrate 83/17.

EXAMPLE 4 N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Oxo-54-2{N-morpholinyl}ethyloxy)phenyl!N-Benzyl Pentanamide ##STR21## STEP A:

N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of N-3-(3-pyridyl)propanoyl!4-(L-valyl)amino-2,2-difluoro-3-hydroxy-5(4-hydroxy)phenyl!N-benzyl pentanamide (0.17 g, 0.29 mmol) in anhydrousdioxane (20 ml) was added anhydrous cesium carbonate (0.325 g), 1 mmol)potassium iodide (0.01 g) and N-2-chloroethyl morpholine hydrochloride(0.075 g, 0.40 mmol). This mixture was heated under reflux overnight.The crude mixture was evaporated in vacuo and the residue was purifiedby flash chromatography (silica gel, gradient of dichloromethane:methylalcool: 98:2 to 92:8).

The title compound was isolated as a white solid (75% yield, (0.15 g).Rf: 0.49 (dichloromethane/methyl alcohol: 9:1) MS: MH!⁺ =696

STEP B:

N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Oxo-54(2-{N-Morpholinyl}Ethyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of oxalyl chloride (0.254 g, 2 mmol) in anhydrousdichloromethane under nitrogen at -60° C., was added a solution ofdimethyl sulfoxide (0.312 g, 4 mmol) in anhydrous dichloromethane (2ml). After 10 minutes stirring at -60° C., a solution of N3-(3-pyridyl)propanoyl!4-(L-valyl)amino-2,2-difluoro-3-hydroxy-54(2-{N-morpholyl}ethyloxy)phenyl!N-benzyl pentanamide (0.14 g, 0.20mmol) in anhydrous dichloromethane (5 ml) was added.

The mixture was stirred at -60° C. under nitrogen for 4 hours and thenthe temperature was allowed to rise to -10° C. Triethylamine (0.303 g, 3mmol) in anhydrous dichloromethane (1 ml) was then added and the mixturewas stirred under nitrogen for 15 hours, while the temperature wasallowed to rise to room temperature. The crude mixture was taken off inethylacetate (50 ml) and washed with water (3×10 ml) and brine (10 ml)then dried over anhydrous magnesium sulphate.

Filtration and removal of the solvent in vacuo a residue which waspurified by flash chromatography (silica gel, gradient ofdichloromethane/methanol: 98:2 to 92:8). The title compound was isolatedas a pale yellow solid (10% yield, 0.014 g). Rf: 0.51(dichloromethane/methanol: 9:1) MS: MH!⁺ =694

EXAMPLE 5 N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Oxo-54({2-pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide ##STR22## STEP A:

4-(L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-5 (4-(Benzyloxy)Phenyl!N-BenzylPentanamide

A solution of4(N-tert-butoxycarbonyl-L-valyl)amino-3,3-difluoro-3-hydroxy-5(4-benzyloxy)phenyl!N-benzyl pentanamide (1.28 g, 2 mmol) in formic acid(50 ml) was stirred at room temperature for 4 hours. The solvent wasremoved in vacuo and the residue was dissolved in ethyl acetate (100 ml)and washed three times with a saturated solution of sodium carbonate(3×30 ml), once with brine (30 ml). The organic layer was dried overanhydrous magnesium sulphate.

Filtration and removal of the solvent in vacuo yielded the titlecompound as a white solid (0.90 g, 84% yield), used without purificationin the next step.

STEP B:

N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-5(4-Benzyloxy)Phenyl!N-Benzyl Pentanamide

To a solution of 3-(3-pyridyl)propionic acid (0.242 g, 1.6 mmol) inanhydrous acetonitrile (10 ml) was added N-methyl morpholine (0.182 g,1.8 mmol) in anhydrous acetonitrile (1 ml). The mixture under nitrogenwas cooled to -20° C. and isobutylchloroformate (0.218 g, 1.6 mmol) inanhydrous acetonitrile (2 ml) was added. After 10 minutes stirring at-20° C. under nitrogen, 4-(L-valyl)amino-2,2-difluoro-3-hydroxy-5(4-benzyloxy)phenyl!N-benzyl pentanamide (0.9 g, 1.6 mmol) in anhydrousN,N-dimethyl formamide (10 ml) was added.

The mixture was stirred at -20° C. under nitrogen for 4 hours and thenthe temperature was allowed to rise to room temperature overnight. Thecrude mixture was evaporated in vacuo and the residue was purified byflash chromatography (silica gel, gradient of dichloromethane/methylalcohol: 99:1 to 92:8). The title compound was obtained as a white solid(0.8 g, 75% yield). Rf: 0.36 (dichloromethane/methanol: 92:8) MS: MH!⁺=673 Analysis: for C₃₆ H₄₂ N₄ O₅ F₂, Calculated: C, 66.95; H, 6.36; N,8.22 Found: C, 66.71; H, 6.19; N, 8.04

STEP C:

N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-5(4-Hydroxy)Phenyl!N-Benzyl Pentanamide

A solution of N3-(3-pyridyl)propanoyl!4-(L-valyl)amino-2,2-difluoro-3-hydroxy-5(4-benzyloxy)phenyl!N-benzyl pentanamide (0.43 g, 0.64 mmol) in absoluteethanol (20 ml) and N,N-dimethylformamide (5 ml) was stirred with 10%palladium on charcoal (0.12 g) at room temperature under atmosphericpressure of hydrogen overnight.

Filtration of the catalyst and evaporation in vacuo of the filtrate,yielded 81% the title compound (0.3 g) as a white solid. Rf: 0.20(dichloromethane/methanol: 92:8) MS: MH!⁺ =582

STEP D:

3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-54({2-pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide

To a solution of N3-(3-pyridyl)propanoyl!4-(L-valyl)amino-2,2-difluoro-3-hydroxy-5(4-(hydroxy)phenyl!N-benzyl pentanamide (0.3 g, 0.51 mmol) in anhydrousdioxane (50 ml) was added anhydrous cesium carbonate (0.43 g, 1.3 mmol)potassium iodide (10 mg) and 2-picolyl chloride (0.108 g, 0.66 mmol).This mixture was heated under reflux for 30 hours. The crude mixture wasdiluted with ethyl acetate (100 ml) and washed three times with water(3×20 ml) and once with brine. The organic layer was dried overanhydrous magnesium sulphate.

Filtration and evaporation in vacuo of the solvent afforded a residuewhich was purified by flash chromatography (silica gel, gradient ofdichloromethane/methyl alcohol: 98:2 to 92:8). The title compound wasisolated as a white solid (41% yield, 0.140 g). Rf: 0.47(dichloromethane/methanol: 9:1) MS: MH!⁺ =674 Analysis: for C₃₇ H₄₁ N₅O₅ F₂, Calculated: C, 65.96; H, 6.13; N, 10.39 Found: C, 64.13; H, 5.87;N, 10.11 ¹⁹ F NMR: shows mixture of stereoisomers 80/20.

STEP E:

N 3-(3-Pyridyl)Propanoyl!4-(L-Valyl)Amino-2,2-Difluoro-3-Oxo-54({2-pyridyl}methyloxy)phenyl!N-Benzyl Pentanamide

To a solution of oxalyl chloride (0.085 g, 0.67 ml) in anhydrousdichloromethane (5 ml) under nitrogen at -60° C., was added a solutionof dimethylsulfoxide (0.11 g, 0.70 mmol) in anhydrous dichloromethane (2ml). After 10 minutes stirring at -60° C., a solution of N3-(3-pyridyl)propanoyl!4-(L-valyl)amino-2,2-difluoro-3-hydroxy-54({2-pyridyl}methyloxy)phenyl!N-benzyl pentanamide (0.045 g, 0.067 mmol)in anhydrous dichloromethane (3 ml) was added. The mixture was stirredat -60° C. under nitrogen for 4 hours and then the temperature wasallowed to rise to -10° C. Triethylamine (0.202 g, 2 mmol) in anhydrousdichloromethane (2 ml) was then added, and the mixture was stirred for15 hours, while the temperature was allowed to rise to room temperature.The crude mixture was taken off in ethyl acetate (50 ml) and washed with0.1N aqueous hydrochloric acid (3×10 ml). The organic layer was washedwith water brine and dried over magnesium sulphate.

After filtration and removal of the solvent in vacuo the residue waspurified by flash chromatography (silica gel, gradient ofdichloromethane/methyl alcohol): 98:2 to 95:5). The title compound wasisolated as a white solid 44% yield, 0.019 g). Rf: 0.50(dichloromethane/methanol: 9:1) MS: MH!⁺ =672

EXAMPLE 6 N-4-(N-Benzyloxycarbonyl-L-valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-{2-N-morpholinyl}ethyloxy)phenyl-pentyl!-O-benzyl-D-valinol##STR23## STEP A:

4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-5-(4-Hydroxy)PhenylPentanoic Acid, Ethyl Ester

A solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-(4-benzyloxy)phenyl!N-benzyl pentanamide (0.719 g, 1.5 mmol) in ethanol(50 ml) was kept for 7.5 hours under an hydrogen atmosphere in thepresence of 10% palladium on charcoal (0.074 g). The hydrogen atmospherewas exchanged by a nitrogen atmosphere, the suspension was filtered offand the solution concentrated in vacuo. The title derivative thusobtained was used as such in the next step (0.500 g, 83% yield). Rf:0.51 (silica gel, petroleum ether/ethyl acetate: 1/1).

STEP B:

N-Tert-Butoxycarbonyl-D-Valinol

A solution of D-valinol (5.1 g, 49.4 mmol) and di-tert-butyldicarbonate(10.9 g, 52 mmol) in methanol (60 ml) was stirred for 17 hours at roomtemperature. After concentration in vacuo, the residue was purified byflash chromatography (silica gel, ethyl acetate/petroleum ether: 3/7,Rf: 0.37) to give the title compound in quantitative yield (10.07 g,colorless oil). MS: MH⁺ =204.

STEP C;

N-Tert-Butoxycarbonyl-O-Benzyl-D-Valinol

To a solution of N-tert-butoxycarbonyl-D-valinol (10 g, 49.3 mmol) andbenzylbromide (5.86 ml, 49.3 mmol) in anhydrous dimethyl formamide (50ml) was added at -5° C. and under nitrogen, potassium-tert-butoxide(11.06 g, 98.6 mmol) as a solid, portionwise, an in such a way that theinternal temperature does not exceed +5° C. The reaction mixture wasstirred for 2 hours at 0° C., diluted with ethyl acetate (2×300 ml),extracted with a 1N solution of potassium hydrogenosulfate (50 ml) andwater (250 ml) and washed twice with water (2×200 ml). After drying ofthe organic phase on sodium sulfate, filtration and concentration invacuo, the resulting oil was purified by flash chromatography (silicagel, ethyl acetate/petroleum ether: 1/9, Rf: 0.42) to give the titlecompound as a colorless oil (9.95 g, 69% yield). MS: MH!⁺ =294.

STEP D:

O-Benzyl-D-Valinol

A solution of N-tert-butoxycarbonyl-O-benzyl-D-valinol (9.95 g, 34 mmol)in formic acid (50 ml) was stirred for 4 hours at room temperature.After removal of the formic acid in vacuo, the sticky residue wasdissolved in water (100 ml), neutralized with a saturated solution ofsodium bicarbonate (100 ml) and the organic material extracted twicewith ethyl acetate (2×200 ml). The organic phases were washed untilneutral with water (2×200 ml) and the combined organic layers were driedon sodium sulfate. Filtration and evaporation of the solvent in vacuoafforded the title amine as a slightly yellowish oil (5.20 g, 79%). MS:MH!⁺ =194.

STEP E:

N-4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-Hydroxy)Phenyl-Pentyl!O-Benzyl-D-Valinol

The title compound is obtained from the compounds described in Example6, Steps A and D, following the method given in Example 1, Step A.

STEP F:

N-4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Benzyl-D-Valinol

The title derivative is obtained from the phenol of Example 6, Step Eand N-(2-chloroethyl)morpholine, hydrochloride using the procedure ofExample 1, Step E.

STEP G:

N-4-Amino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Benzyl-D-Valinol

The title amine is prepared from the compound of Example 6, Step F usingthe deprotection procedure described in Example 1, Step B.

STEP H:

N-4-(N-Butoxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Benzyl-D-Valinol

The title compound is obtained from the amine of Example 6, Step G andN-benzyloxycarbonyl-L-valyl anhydride following the procedure given inExample 1, Step C.

STEP I:

N-4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-1,3-Dioxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-BenzylValinol

The title derivative is obtained from the alcohol of Example 6, Step Husing the oxidation method described in Example 1, Step H.

EXAMPLE 7 N-4-(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-1,3-Dioxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Methyl-D-Valinol##STR24## STEP A:

N-Tert-Butoxycarbonyl-O-Methyl-D-Valinol

The title compound has been prepared in 67% yield from the alcohol ofExample 6, Step B and methyl iodide following the alkylation methodgiven in Example 6, Step C. Rf: 0.27 (silica gel, ethylacetate/petroleum ether: 1/9).

STEP B:

O-Methyl-D-Valinol

A solution of compound of Example 7, Step A (1.9 g, 8.76 mmol) in drydiethyl ether saturated with HCl gas was kept for 2 hours at roomtemperature. The solvent was removed in vacuo. The residue was dissolvedin a minimum amount of a 95/5 mixture of dichloromethane anddiethylamine and purified by flash chromatography on silica gel usingthe same mixture of solvents. The title amine was obtained in 59% yield.Rf: 0.01 (ethyl acetate/methanol: 8/2).

STEP C:

N-4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-Hydroxy)Phenyl-Pentyl!O-Methyl-D-Valinol

The title derivative is obtained from the compound of Example 6, Step Aand the amine of Example 7, Step B following the reaction proceduregiven in Example 1, Step A (79% yield). Rf: 0.16 (ethylacetate/petroleumether: 4:6) MS: MH!⁺ =461.

STEP D

N-4-Tert-Butoxycarbonylamino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Methyl-D-Valinol

The title compound is prepared from the phenol of Example 7, Step C andN-(2-chloroethyl)morpholine, hydrochloride using the method described inExample 1, Step E (58% yield). Rf: 0.18 (ethylacetate).

STEP E:

N-4-Amino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Methyl-D-Valinol

The title amine is obtained from the compound of Example 7, Step D usingthe deprotection method given in Example 1, Step B (85% yield).

STEP F:

N-4(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-3-Hydroxy-1-Oxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Methyl-D-Valinol

The title alcohol is obtained from the amine of Example 7, Step E andN-benzyloxycarbonyl-L-valyl anhydride using the coupling procedure givenin Example 1, Step C (78% yield). Rf: 0.24 (dichloromethane/methanol:95:5) MS: MH!⁺ =707 Analysis: for C₃₆ H₅₂ N₄ O₈ F₂, 0.5 H₂ O Calculated:C, 60.40; H, 7.46; N, 7.83 Found: C, 60.29; H, 7.36; N, 7.78

STEP G:

N-4(N-Benzyloxycarbonyl-L-Valyl)Amino-2,2-Difluoro-1,3-Dioxo-5-(4-{2-N-Morpholinyl}Ethyloxy)Phenyl-Pentyl!O-Methyl-D-Valinol

A mixture of the alcohol of example 7, step F (0.130 g, 0.184 mmol),1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess Martinperiodane, 0.312 g, 0.736 mmol) and tert-butanol (0.035 ml, 0.368 mmol)in freshly distilled dichloromethane (over phosphorus pentoxyde, 5 ml)is stirred for 15 minutes at room temperature. The reaction mixture ishydrolyzed with isopropanol (0.6 ml) and concentrated in vacuo. Theresidue is suspended in dichloromethane (1.5 ml), filtered through aFluoropore filter which is rinsed twice with dichloromethane (2×1 ml)and the filtrate is concentrated in vacuo (0.335 g). Purification byflash chromatography (silica gel, dichloromethane/methanol: 98:2 toremove the byproducts coming from the Dess Martin reagent, then 96:4 torecover the title ketone (0.109 g) and impure ketone largelycontaminated with the starting alcohol (0.121 g). These impure materialhas been oxidized a second time following the above procedure to givemore ketone (0.099 g). The combined batches (0.208 g) are crystallizedfrom ethylacetate/pentane to give the title ketone in 69% yield. Rf: 0.1(dichloromethane/methanol: 95:5) MS: MH!⁺ =704 Analysis: for C₃₆ H₅₀ N₄O₈ F₂, 0.75 H₂ O Calculated: C, 60.20; H, 7.23; N, 7.80 Found: C, 60.28;H, 7.26; N, 7.94

The compounds of the present invention are useful as inhibitors ofretroviral proteases required for replication, particularly the HIV-1and HIV-2 viral proteases, the prevention or treatment of infection bythe human immunodeficiency virus (HIV), and the treatment of consequentpathological conditions such as the acquired immunodeficiency syndrome(AIDS) in mammals capable of being infected with HIV virus. TreatingAIDS, preventing infection by HIV or treating infection by HIV, isdefined as including, but not limited to, treating a wide range ofstates of HIV infection: AIDS, ARC (AIDS related complex), bothsymptomatic and asymptomatic, and actual or potential exposure to HIV.For example, the compounds of this invention are useful in preventinginfection by HIV after suspected past exposure to HIV by, e.g., bloodtransfusion, accidental needle stick, or exposure to patient bloodduring surgery.

The term "stereoisomers" is a general term for all isomers ofindividuals molecules that differ only in the orientation of their atomsin space. It includes mirror image isomers (enantiomers), geometric(cis/trans) isomers, and isomers of compounds with more than one chiralcenter that are not mirror images of one another (diastereoisomers). Foramino-acids, the designations L/D, or R/S can be used as described inIUPAC-IUB Joint Commission on Biochemichal Nomenclature, Eur. J.Biochem. 138: 9-37 (1984).

For these purposes, the compounds of the present invention may beadministered orally, parenterally (including subcutaneous injections,intravenous, intramuscular, transdermal, intrasternal injection orinfusion techniques), by inhalation spray, or rectally, in dosage unitformulations containing convention non-toxic pharmaceutically acceptablecarriers, adjuvants and vehicles.

Thus, in accordance with the present invention there is further provideda method of treating and a pharmaceutical composition for treating HIVinfection and AIDS. The treatment involves administering to a patient inneed of such treatment a pharmaceutical composition comprising apharmaceutical carrier and a therapeutically effective amount of acompound of the present invention, or a pharmaceutically acceptable saltthereof.

These pharmaceutical compositions may be in the form oforally-administrable suspensions or tablets; nasal sprays; sterielinjectable preparations, for example, as sterile injectable aqueous oroleagenous suspensions or suppositories) or they may be administeredtransdermally.

When administered orally as a suspension, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetener/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, thesecompositions may be prepared by mixing the drug with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters or polyethylene glycols, which are solid at ordinarytemperatures, but liquidize and/or dissolve in the rectal cavity torelease the drug.

Dosage levels of the order of 0.02 to 5.0 or 10.0 grams per day areuseful in the treatment or prevention of the above-indicated conditions,with oral doses being higher. For example, infection by HIV iseffectively treated by the administration of from 1 to 50 milligrams ofthe compound per kilogram of body weight from one to three times perday. It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination the severity ofthe particular condition, and the host undergoing therapy. Preferredcompounds are when P₂ is C₁₋₆ alkyl and especially C₁₋₃ alkyl, W and/orW' are C₁₋₃ alkyl, and/or R and/or R' are morpholinyl, C₁₋₄ alkylenyl orpiperidyl.

The present invention is also directed to combinations of the HIVprotease-inhibitory compounds with one or more agents useful in thetreatment of AIDS, such as, for example, with known antiviral agentssuitable for treating HIV 1 and HIV 2 viral infections, e.g., AZT, withor without a PNPase inhibitor, or in conjunctive therapy with DDI and aPNPase inhibitor.

The compounds of this invention may be assayed for their HIV-proteaseinhibition using the following published techniques.

Preparation of Retroviral Enzyme and Assay for Inhibition of theProtease

A) Preparation of Retroviral Enzyme

To prepare the recombinant protease, the HIV protease was expressed viaE. Coli by the published work of C. Guenet, et al., in European Journalof Pharmacology, Molecular Pharmacology Section, 172 (1989) 443-451.

B) Assay for Inhibition of Recombinant Viral Protease

Inhibition of the reaction of the protease with a peptide substrateSer-Gln-Asn-Tyr-Pro-Ile-Val-NH₂, Km=1 mM were in 50 mM Na acetate, 10%glycerol, 5% ethyleneglycol, pH 5.5, at 37° C. for 1 hour. Variousconcentrations of inhibitor in 10 μl DMSO were added to 80 μl of assaysolution and the reaction initiated by the addition of 10 μl (1.6 μg) ofrecombinant protease. The reaction was quenched with 16 μl of 4Mperchloric acid. Products of the reaction were separated by HPLC (VYDACwide pore 5 cm C-18 reverse phase, acetonitrile gradient, 0.1%trifluoroacetic acid). The extent of inhibition of the reaction wasdetermined from the peak heights of the products. HPLC of the products,independently synthesized, provided quantitation standards andconfirmation of the product composition.

By following the techniques referenced above, as well as by utilizationof other known techniques, as well as by comparison with compounds knownto be useful for treatment of the above-mentioned disease states, it isbelieved that adequate material is available to enable one of ordinaryskill in the art to practice the invention.

As is true for most classes of compounds found to be useful in thepharmaceutical industry, certain subgeneric groups and certain specificcompounds are more preferred such as those exemplified and shown in thefollowing charts.

    __________________________________________________________________________    R.sub.1  P.sub.2                                                                             P.sub.1       R.sub.6 = H, R.sub.5                             __________________________________________________________________________    benzyl   isopropyl                                                                           4- (3-pyridyl)methyloxy!benzyl                                                              benzyl                                           3-pyridylethyl                                                                         isopropyl                                                                           4-pentenyl    2-pyridylmethyl                                  benzyl   isopropyl                                                                           4- (2-pyridyl)methyloxy!benzyl                                                              benzyl                                           benzyl   isopropyl                                                                           4- (2-pyridyl)methyloxy!benzyl                                                              2-pyridylmethyl                                  benzyl   isopropyl                                                                           4- (3-pyridyl)methyloxy!benzyl                                                              2-pyridylmethyl                                  (3-pyridyl)ethyl                                                                       isopropyl                                                                           4- (3-pyridyl)methyloxy!benzyl                                                              benzyl                                           benzyl   t-butyl                                                                             4- (2-pyridyl)methyloxy!benzyl                                                              3-pyridylmethyl                                  benzyl   t-butyl                                                                             4- (3-pyridyl)methyloxy!benzyl                                                              1 #STR25##                                       (2-pyridyl)ethyl                                                                       isopropyl                                                                           4- (3-pyridyl)methyloxy!benzyl                                                              1 #STR26##                                       2 #STR27##                                                                             phenyl                                                                              4- (3-pyridyl)methyloxy!benzyl                                                              benzyl                                           benzyl   isopropyl                                                                           4- (4-pyridyl)methyloxy!benzyl                                                              benzyl                                           benzyl   isopropyl                                                                           4- (2-pyridyl)methyloxy!benzyl                                                              3 #STR28##                                       (3-pyridyl)ethyl                                                                       isopropyl                                                                           4- (3-pyridyl)methyloxy!benzyl                                                              benzyl                                           benzyl   isopropyl                                                                           4- 2-(N-morpholyl)ethyloxy!                                                                 3-pyridylmethyl                                                 benzyl                                                         (2-pyridyl)ethyl                                                                       cyclopentyl                                                                         4- 2-(N-morpholyl)ethyloxy!                                                                 benzyl                                                          benzyl                                                         benzyl   isopropyl                                                                           4- 2-(N-morpholyl)ethyloxy! benzyl                                                          4 #STR29##                                       benzyl   isopropyl                                                                           4- 2-(N-morpholyl)ethyloxy!                                                                 2-pyridylmethyl                                                 benzyl                                                         benzyl   isopropyl                                                                           4- 2-(N-morpholyl)ethyloxy! benzyl                                                          5 #STR30##                                       benzyl   isopropyl                                                                           4- 2-(N-morpholyl)ethyloxy!                                                                 2-pyridylmethyl                                                 benzyl                                                         benzyl   t-butyl                                                                             4- 2-(N-morpholyl)ethyloxy! benzyl                                                          6 #STR31##                                       benzyl   t-butyl                                                                             4- 2-(N-morpholyl)ethyloxy! benzyl                                                          7 #STR32##                                       (3-pyridyl)ethyl                                                                       isopropyl                                                                           4- 2-(pyridyl)methyloxy!benzyl                                                              6 #STR33##                                       (3-pyridyl)ethyl                                                                       isopropyl                                                                           4- 3-(pyridyl)methyloxy!benzyl                                                              6 #STR34##                                       (3-pyridyl)ethyl                                                                       t-butyl                                                                             4- 4-(pyridyl)methyloxy!benzyl                                                              6 #STR35##                                       benzyl   isopropyl                                                                           4- 2-(pyridyl)methyloxy!benzyl                                                              6 #STR36##                                       (3-pyridyl)ethyl                                                                        isopropyl                                                                          4- 2-(pyridyl)methyloxy!benzyl                                                              8 #STR37##                                       benzyl   isopropyl                                                                           4- 2-(N-morpholyl)ethyloxy! benzyl                                                          9 #STR38##                                       (2-pyridyl)ethyl                                                                       isopropyl                                                                           4- 3-(pyridyl)methyloxy!benzyl                                                              0 #STR39##                                       benzyl   isopropyl                                                                           4- 2-(N-piperidyl)ethyloxy! benzyl                                                          1 #STR40##                                       (3-pyridyl)ethyl                                                                       isopropyl                                                                           4- (2-pyridyl)methyloxy)benzyl                                                              2 #STR41##                                       benzyl   isopropyl                                                                           4- (2-N-morpholyl)ethyloxy! benzyl                                                          3 #STR42##                                       benzyl   phenyl                                                                              4- (2-N-morpholyl)ethyloxy! benzyl                                                          4 #STR43##                                       (3-pyridyl)ethyl                                                                       isopropyl                                                                           4- (2-N-morpholyl)ethyloxy! benzyl                                                          5 #STR44##                                       __________________________________________________________________________

What is claimed is:
 1. A compound of Formula 1 ##STR45## and thestereoisomers, hydrates, isosteres and the pharmaceutically acceptablesalts thereof whereinP₁ is ##STR46## wherein T is (O)_(b) --W--R and T'is (O)_(b') --W'-R'! or H, wherein each of W and W' are independentlyC₁₋₆ alkylene or nothing,provided that W is C₂₋₆ alkylene when W isdirectly attached to a nitrogen atom in R, provided that W' is C₂₋₆alkylene when W' is directly attached to a nitrogen atom in R'; P₂ isC₁₋₆ alkyl, cyclopentyl, hydroxy C₁₋₆ alkyl, phenyl, benzyl- or3-tetrahydrofuryl; R and R' are each independently C₂₋₆ alkenyl,piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl,pyrazinyl, or pyrimidinyl, wherein substituted piperazinyl ispiperazinyl substituted on one nitrogen atom thereof with CHO, C(O)NHR₄,C₁₋₄ alkyl or CO₂ R₄ ; R₁ is benzyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, phenyl,benzyl, phenethyl, fluorenylmethylenoxy, 2-quinolinyl, PDL, ##STR47##NHSO₂ R₄, N(R₄)(benzyl), or N(R₄)(PDL); PDL is --(CH₂)_(a) -2-, 3-, or4-pyridyl, or p-substituted benzyloxy, wherein the substitution is witha nitro, OH, amino, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkylene, or halogeno; R₃is C₂₋₆ alkenyl, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkyl, C₁₋₆ alkyl, or OH; R₄is H, C₁₋₆ alkyl, phenyl or benzyl; R₅ is H, C₁₋₆ alkyl, OH, C₁₋₆alkoxy, ##STR48## .paren open-st.C₁₋₆ alkylene.paren close-st.OR₄ or--CH(Y)(Z), Y being C₁₋₆ hydroxy alkylene, C₁₋₆ alkyl, or (CH₂ .parenclose-st._(e) --C₆ H₄ .paren open-st.V)_(a), andZ being CHO, CO₂ R₄,CONHR or (CH₂ .paren close-st._(e) --OR₄, and V being OR₄ or hydroxyC₁₋₆ alkylene, R₆ is as defined for R₅ with the proviso that R₆ is otherthan H when R₅ is H, and when R₅ and R₆ are taken together with nitrogenatom to which they are attached form a heterocyclic moiety of theformulae ##STR49## R₇ is CH₂ OR₄, C(O)NHR₄ or CHO, R₈ is (H,OH) or ═O; ais zero, 1, 2 or 3; b and b' are each independently zero or 1; d and d'are each independently 1 or 2; e and e' are each independently zero, 1or 2; and x is zero or one.
 2. The compound of claim 1 wherein x is one.3. The compound of claim 2 wherein P₁ is ##STR50##
 4. The compound ofclaim 1 wherein b is
 1. 5. The compound of claim 1 wherein T' ishydrogen.
 6. The compound of claim 1 wherein b is 1, W is C₁₋₃ alkylene,and R is morpholinyl and T' is hydrogen.
 7. The compound of claim 1wherein b is 1, W is C₁₋₃ alkylene, and R is pyridyl and T' is hydrogen.8. The compound of claim 1 wherein b is 1, W is C₁₋₃ alkylene, and R isethenyl and T' is hydrogen.
 9. The compound of claim 1 wherein W is C₁₋₂alkylene.
 10. The compound of claim 1 wherein P₂ is C₁₋₆ alkyl.
 11. Thecompound of claim 1 wherein P₂ is C₁₋₃ alkyl.
 12. The compound of claim1 wherein R₁ is benzyloxy.
 13. The compound of claim 1 wherein R₁ isPDL.
 14. The compound of claim 1 wherein R₅ is H and R₆ is benzyl. 15.The compound of claim 1 wherein R₅ is H and R₆ is CH(Y)(Z) wherein Y isC₁₋₃ alkyl and Z is --(CH₂)_(e) --OR₄ wherein e is 1 and R₄ is benzyl orC₁₋₃ alkyl.
 16. A process for preparing compound of the formula and thehydrates, isostere and pharmaceutically acceptable salts thereofwhereinP₁ is ##STR51## wherein T is (O)_(b) --W--R! and T' is (O)_(b')--W'--R'! or H, wherein each of W and W' are independently C₁₋₆ alkyleneor nothing,provided that W is C₂₋₆ alkylene when W is directly attachedto a nitrogen atom in R, provided that W' is C₂₋₆ alkylene when W' isdirectly attached to a nitrogen atom in R'; P₂ is C₁₋₆ alkyl,cyclopentyl, hydroxy C₁₋₆ alkyl, phenyl, benzyl or 3-tetrahydrofuryl; Rand R' are each independently C₂₋₆ alkenyl, piperazinyl, substitutedpiperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, or pyrimidinyl,wherein substituted piperazinyl is piperazinyl substituted on onenitrogen atom thereof with CHO, C(O)NHR₄, C₁₋₄ alkyl or CO₂ R₄ ; R₁ isbenzyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, phenyl, benzyl, phenethyl,fluorenylmethylenoxy, 2-quinolinyl, PDL, ##STR52## NHSO₂ R₄,N(R₄)(benzyl), or N(R₄)(PDL) PDL is --(CH₂)_(a) -2-, 3-, or 4-pyridyl,or p-substituted benzyloxy, wherein the substitution is with a nitro,OH, amino, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkylene, or halogeno; R₃ is C₂₋₆alkenyl, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkyl, C₁₋₆ alkyl, or OH; R₄ is H,C₁₋₆ alkyl, phenyl or benzyl; R is H, C₁₋₆ alkyl, OH, C₁₋₆ alkoxy,##STR53## .paren open-st.C₁₋₆ alkylene.paren close-st.OR₄ or --CH(Y)(Z),Y being C₁₋₆ hydroxy alkylene, C₁₋₆ alkyl, or (CH₂ .paren close-st._(e)--C₆ H₄ .paren open-st.V)_(e), andZ being CHO, CO₂ R₄, CONHR₄ or (CH₂.paren close-st._(e) --OR₄, and V being OR₄ or hydroxy C₁₋₆ alkylene, R₆is as defined for R₅ with the proviso that R₆ is other than H when R₅ isH, and when R₅ and R₆ are taken together with nitrogen atom to whichthey are attached form a heterocyclic moiety of the formulae ##STR54##R₇ is CH₂ OR₄, C(O)NHR₄ or CHO, R₈ is (H,OH) or ═O; a is zero, 1, 2 or3; b and b' are each independently zero or 1; d and d' are eachindependently 1 or 2; e and e' are each independently zero, 1 or 2; andx is zero or one which comprises using a compound of the formula##STR55## wherein R₁, P₁, P₂, R₅ and R₆ are defined above, oxidizing thecompound and optionally converting the resulting oxidized compounds to apharmaceutically acceptable salt thereof.
 17. The process according toclaim 16 wherein the oxidation step uses the Dess Martin oxidation. 18.The process according to claim 16 wherein the oxidation step uses theSwern oxidation.
 19. A method of treating infection by the HumanImmunodeficiency Virus in a patient in need of such therapy byadministering to the patient a sufficient amount of the compoundaccording to claim
 1. 20. The method according to claim 19 wherein x isone.
 21. The method according to claim 20 wherein P₂ is isopropyl,t-butyl, cyclopentyl or phenyl.
 22. The method according to claim 20wherein P₁ is 4- (4-pyridyl)methyloxy!benzyl, 4-(3-pyridyl)methyloxy!benzyl, 4- (2-pyridyl)methyloxy!benzyl, 4-2-(N-morpholyl)ethyloxy!benxyl, 4- 2-(N-piperidyl)ethyloxy!benzyl, or4-pentenyl.
 23. The method according to claim 20 wherein R₁ is benzyl,3-pyridyl(ethyl), 2-pyridyl)ethyl), or N-morpholino.
 24. The methodaccording to claim 20 wherein R₆ is hydrogen and R₅ is benzyl,2-pyridylmethyl, N-morpholino, 3-pyridylmethyl, ##STR56##